We have been studying bacteriophages as model systems for the study of such topics as gene regulation, host-virus interaction and macromolecular assembly. We are taking advantage of the base of information of phage genetics and physiology for the purpose of bacteriophage therapy of multi-drug resistant-bacterial pathogens. We chose to work on infections with vancomycin-resistant Enterococcus faecium (VRE) and with K-antigenic E. coli pathogen with the purpose of developing phage for therapy. 1. E. coli-K phage: We isolated a virulent double-stranded DNA bacteriophage, named FK1-5, and found it to be capable of infecting E. coli strains that possess either the K1 or the K5 polysaccharide capsule. Electron micrographs show that the virion consists of a small icosohedral head with short tail spikes, similar to members of the Podoviridae family. DNA sequence analysis of the region encoding the tail fiber protein showed two open reading frames encoding previously characterized hydrolytic phage tail fiber proteins. The first is the K5 lyase protein gene of FK5, which allows this phage to specifically infect K5 E. coli strains. A second open reading frame encodes a protein almost identical in amino acid sequence to the N-acetylneuraminidase (endosialidase) protein of FK1E, which allows this phage to specifically infect K1 strains of E. coli. We demonstrated that mature phage particles contain both tail fiber proteins, and mutational analysis indicates that each protein can be independently inactivated. A comparison of the tail gene regions of FK5, FK1E, and FK1-5 showed that the genes are arranged in a modular or cassette configuration and suggested that this family of phages can broaden host range by horizontal gene transfer. 2. Salmonella phage: The lytic Salmonella phage SP6 encodes a tail protein with a high degree of sequence similarity to the tail protein of the biologically unrelated lysogenic Salmonella phage P22. The SP6 tail gene is flanked by an upstream region that contains a promoter and a downstream region that contains a putative Rho-independent transcription terminator, giving it a cassette or modular structure almost identical to the structure of the tail genes of coli-phages, K1E, K5, and K1-5. It now appears that SP6, K1-5, K5, and K1E are very closely related but have different tail fiber proteins, giving them different host specificities.